The two broad objectives of this research project are to characterize the biochemical nature of the blood-brain barrier (BBB) and to determine the sequence of biochemical events that occur when the brain is deprived of oxygen resulting in cell degeneration and death. The cerebral circulation of the dog will be isolated and perfused with heparinized blood by use of an extracorporeal pump/oxygenator. Unidirectional influx of various metabolites will be studied by the indicator dilution technique using 22Na ion as the intravascular marker and tritium labeled substances as the test compounds. The effect on glucose transport of hyperosmotic solutions and inhibitors of mitochondrial function will be evaluated and an attempt will be made to isolate components of the BBB that are involved in glucose transport. The effect of flow rate and CO2 tension on glucose transport will be examined. Measurements will be made of the contribution of red cell glucose to net brain glucose consumption. The effects of cerebral anoxia and ischemia on transport at the BBB and cerebral metabolism will be determined. Mitochondrial function, nucleotide metabolism, lysosomal activation and cerebral edema will be investigated. Electroencephalographic recordings, new oxygen and glucose consumption, metabolite (lactate and adenosine) efflux and perfusion pressure will be monitored. Amelioration by thiopental of ischemic brain damage will be examined. BBB transport and cerebral metabolism will also be investigated during reperfusion and oxygenation following periods of oxygen deprivation. The effects of cerebral anoxia and ischemia on metabolism, transport and edema formation will be compared.